The immunoglobulin (Ig) gene superfamily comprises a large number of cell surface glycoproteins that share sequence homology with the V and C domains of antibody heavy and light chains. The Ig superfamily molecules function as receptors for antigen, receptors or counter-receptors for other cell surface molecules including other Ig superfamily molecules and adhesion molecules, and as receptors for cytokines (A. F. Williams et al., Annu. Rev. Immunol. 6:381-405, 1988).
Another protein fold motif of this family is the leucine rich repeat (LRR), which is a segment of 20-29 amino acids with a signature pattern of 4 consensus leucines and an asparagine. LRRs most commonly occur in multiple tandem arrays and have been identified in more than 60 different proteins of diverse function (reviewed in B. Kobe and J. Deisenhofer, Trends-Biochem-Sci. 19, 415-21 (1994) and in B. Kobe and J. Deisenhofer, Curr Op in Struct Biol 5, 409-416 (1995)). Examples of this family are found in a range of organisms and include the insulin binding protein acid labile subunit (ALS), the morphogenic protein "18 wheeler," the neural development protein slit, the receptors for chorionic gonadotropin, lutrophin, and follitrophin, and the transcriptional regulator, CIITA. The crystal structure of one member of this family, porcine ribonuclease inhibitor (RI), has been determined (B. Kobe and J. Deisenhofer, Nature 366, 751-756 (1993)) and serves as a model for the folding of the LRR regions in other proteins. RI consists entirely of 15 LRRs which assume a .beta.-strand-turn-helix-turn conformation and assemble into a toroid shaped horseshoe structure. Although diverse in function and cellular localization, a common property of members of the LRR family is protein interaction which in several instances has been mapped to the unusual structural region of the LRRs. One indication of the nature of this interaction is revealed by the structure of the complex between RI-and its non-native ligand ribonuclease A (B. Kobe and J. Deisenhofer, Nature 374, 183-186 (1995)). As revealed in both the complexed and uncomplexed structure, the conserved residues of the LRR repeat are buried, serving as foundations for the fold. The specificity for differential protein recognition lies in other non-conserved residues in the repeat. A second sequence motif often associated with LRRs is a cysteine cluster containing 4 similarly spaced cysteines and a proline residue. These clusters lie immediately N- or C-terminal, or both, to the tandem LRRs, and most frequently occur in proteins associated with adhesion or receptor function. One example of this subfamily is the insulin binding protein acid labile subunit (ALS) (S R Leong et al., Mol Endrocrinol 6, 870-876 (1992)), which forms dimeric complexes with insulin binding proteins (IBP) and trimeric complexes with IBPs and insulin like growth factors (IGFs). These complexes restrict IGFs to the vascular compartment with a long extension of their circulating 1/2 life, and thereby are critical in the development of endocrine function and in the regulation of glucose homeostasis. A second example is the drosophila protein slit, a secreted protein of glial cells, which is involved in the development of axonal pathways (J M Rothberg et al., Genes Develop. 4, 2169-2187 (1990).
Recently, LIG-1, a novel mouse membrane glycoprotein, which contains 15 leucine-rich repeats (LRR) and flanking cysteine clusters and 3 Ig-like domains of the C2-type, was identified by Y. Suzuki et al., J. Biol. Chem. 271:22522-22527, (1996). LIG-1 is expressed predominantly in the mouse brain, restricted to a small subset of glial cells such as the Bergmann glial cells and those in the nerve fiber layer of the olfactory bulb. Based on its unique molecular structure and tissue-specific expression, LIG-1 may play a role in neuroglial differentiation, development, and/or maintenance of neural function. This indicates that these receptors have an established, proven history as therapeutic targets. Clearly there is a need for identification and characterization of further receptors which can play a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, neurological disorders such as Alzheimer's disease, multiple sclerosis and abnormal neural development; endocrine disorders such as diabetes; and heart disease.